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TranScrip Critically Reviews and Supports the GAIN Act (Generating Antibiotic Incentives Now), IMI (Innovative Medicines Initiative) 6th Call and Other Recent Initiatives that Could Kick-Start Much Needed Antibiotic Development and are an Important Step in the Right Direction

August 3, 2012 -- Barriers in discovery, development, regulations and economics must be overcome if we are to see much needed new antibacterial agents reach the market with indications that are relevant to current and future emerging bacterial resistances1,2,3.

The Gain Act, IMI’s 6th Call and other recent initiatives designed to increase the chances of bringing new antibacterials to patients to combat seriously threatening resistant infections are moves in the right direction but TranScrip believe more will be needed. The new initiatives, their intent and scope and what might also be in store in the future are reviewed in this article.

Pronouncements, publications, lobbying and calls for action have come particularly from major influential bodies including the Infectious Disease Society of America (IDSA), the Alliance for the Prudent Use of Antibiotics (APUA), ReAct, and the British Society for Antimicrobial Chemotherapy (BSAC), and the World Health Organisation (WHO) which stated that “Antibiotic resistance is becoming a public health emergency of yet unknown proportions”4. However, 2012 has at last seen developments indicating that steps are now being taken to address some of the barriers; the GAIN act in the US and the closing of the IMI antibiotic call in the last month to name but two.

Whilst stimulation and funding of discovery research is obviously critical, it is only recently that the subsequent high attrition rate and lack of success at the clinical trial and regulatory stage has been increasingly highlighted as a concern. In 2009, of the 15-16 antibiotics in clinical development, 8 had activity against the key bacteria causing emerging clinical problems (the Gram-negatives organisms) and for which there are limited treatment options but none against the bacteria resistant to all currently available drugs, the so-called ‘ESKAPE’ organisms5,6. In 2011 there were only 10 compounds in clinical development against the Gram-negatives and no trials running in the important area of hospital-acquired pneumonia or ventilator-associated pneumonia (HAP/VAP), and no antibiotic in development with activity against bacteria resistant to all currently available drugs7. Increasingly antibacterials have been registered for limited indications, and not for areas of high resistance and unmet need, or for broad-spectrum use such as community respiratory pathogens8,9.

Most submissions target the FDA in the USA for the first registration and it is here where newly approved legislation may offer an additional incentive for the development and registration of antibacterials. The GAIN (Generating Antibiotic Incentives Now) Act which failed to pass when first proposed in 2010, was approved by the US Senate on the 26th June 2012 and aims to grant speedier application reviews for certain experimental treatments against infectious disease, and extend market exclusivity by an additional five years10. The current exclusivity period is not thought to be long enough for companies to consider antibiotic R&D as profitable. Although welcome, there are views that more is needed and that the legislation is not likely to have the intended consequences11. Priority regulatory review will give an early initial FDA opinion regarding the drug’s chances for approval but not a simpler path to, or an increased probability of approval. The extended period of exclusivity may still be insufficient and relies on the incentive of company returns on investment in an area where, critically, antibacterial pricing continues to remain too low relative to other treatment types whilst the benefits can be greater12. The GAIN Act is a positive move but more is needed to provide other ‘push’ (grants to undertake early R&D) and ‘pull’ incentives (rewards and benefits for bringing new antibiotics to market in areas of unmet need and low financial return) as well as public/private shared risk and funding strategies3,13,14. The Act also relies on new agents getting to the market despite regulatory hurdles. Additional action is needed to reduce the costs and uncertainties of the regulatory process and to which end Europe has moved a step further.

The European Medicines Agency (EMA) has released a draft addendum to the guidelines on the requirements for clinical studies related to specific indications and on clinical development programmes for new antibacterial agents targeted against rare or multidrug-resistant pathogens15.

This is a response to requests for more detailed guidance on issues such as patient selection criteria and primary endpoints, including efficacy variables and the timing of the assessment of outcomes. This request was made by the pharmaceutical industry and academia during previous consultation on the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections, and will be subject to further consultation before finalisation in 2013.

The EMA initiative has been welcomed by APUA who point out that key elements are that patients can be enrolled in trials after receipt of a dose of prior antibiotic therapy (increasing the ability to include resistant organisms), the possibility of conducting organism-specific rather than disease-specific studies, the possibility of conducting small studies to support approval of antibiotics that treat resistant infections and clinical response endpoints at test-of-cure 16. None of these principles have been incorporated into FDA guidances to date.

In response to the short-comings of the then proposed GAIN act, and echoing the elements of the EMA draft addendum, IDSA have been lobbying for the last two years as their highest priority recommendation for the establishment of a Limited Population Antibacterial Drug (LPAD) approval mechanism {(previously Special Population Limited Medical Use (SPLMU)}17. They believe that this is a necessary complement to the GAIN Act enabling companies to access the economic incentives included in the Act and is endorsed by many pharmaceutical companies. LPAD will add a new approval mechanism for antibacterial drugs to treat the most serious bacterial infections where there exists an unmet medical need and help to provide a feasible and predictable approval process. Under the LPAD mechanism, a drug’s safety and effectiveness would be studied in substantially smaller, more rapid, and less expensive clinical trials and would lead to an indication for use in small, well-defined populations of patients for whom the drugs’ benefits have been shown to outweigh their risks. The LPAD mechanism will not be used to approve antibacterial products that treat more common infections or where sufficient alternatives exist.

Along with moves to incentivise and simplify the process for bringing new agents to market the EUs Innovative Medicines Initiative (IMI) 6th Call New Drugs 4 Bad Bugs (ND4BB) will result in a coordinated platform for accelerating and refining antibiotic innovation and development pathways, and the sharing of resources, costs and risks18. IMI will potentially address the issue of how antibacterial clinical trials are designed, conducted, and coordinated with best efficacy, in an environment where costs are escalating and Pharma infrastructures are diminishing.

These initiatives to provide incentives to bring new antibacterials to market, coupled with public/private development and funding partnerships, and feasible and predictable regulatory pathways are welcome and an important step in the right direction. Further extension of these initiatives and their adoption in the US and Europe may start to have the desired effect of bringing new antibacterials to patients to combat emerging resistant infections, and fending off the ‘public health emergency of yet unknown proportions’ anticipated by the WHO.

3.White AR, Effective antibacterials: at what cost? The economics of antibacterial resistance and its control J Antimicrob Chemother 2011; 66: 1948–1953

4.WHO. Towards a strategy on the containment of antibiotic resistance in the WHO European area.7th April 2011. http://www.euro.who.int/en/who-we-are/whd/past-themes-of-world-healthday/world-health-day-2011-antibiotic-resistance-no-action-today,-no-curetomorrow/presentations/towards-a-strategy-on-the-containment-of-antibiotic-resistance-in-thewho-european-region-generic-presentation.

8.Gabbay F. How do we get the antibiotics we need? Opportunities and challenges posed and lessons learned from recent submissions. 24th Annual EuroMeeting, DIA, 26-28th March 2012, Copenhagen,Denmark. 2012.

9. Gabbay F. How do we get the antibiotics we need? Opportunities and challenges and lessons learned from recent submissions. 1st Annual Symposium of Bacteriology and Infection (SBI), Beijing, China,30th July-1st August. 2011.